Loss of Phospholipid Asymmetry and Surface Exposure of Phosphatidylserine Is Required for Phagocytosis of Apoptotic Cells by Macrophages and Fibroblasts*

By Valerie Fadok, Aimee de Cathelineau, D. Daleke, P. Henson, D. Bratton. Journal of Biological Chemistry, 2001

684 citations recorded by the source corpus.

Removal of apoptotic cells during tissue remodeling or resolution of inflammation is critical to the restoration of normal tissue structure and function. During apoptosis, early surface changes occur, which trigger recognition and removal by macrophages and other phagocytes. Loss of phospholipid asymmetry results in exposure of phosphatidylserine (PS), one of the surface markers recognized by macrophages. However, a number of receptors have been reported to mediate macrophage recognition of apoptotic cells, not all of which bind to phosphatidylserine. We therefore examined the role of membrane phospholipid symmetrization and PS externalization in uptake of apoptotic cells by mouse macrophages and human HT-1080 fibrosarcoma cells by exposing them to cells that had undergone apoptosis without loss of phospholipid asymmetry. Neither mouse macrophages nor HT-1080 cells recognized or engulfed apoptotic targets that failed to express PS, in comparison to PS-expressing apoptotic cells. If, however, their outer leaflets were repleted with thel-, but not the d-, stereoisomer ofsn-1,2-PS by liposome transfer, engulfment by both phagocytes was restored. These observations directly demonstrate that loss of phospholipid asymmetry and PS expression is required for phagocyte engulfment of apoptotic cells and imply a critical, if not obligatory, role for PS recognition in the uptake process.

Subfields: Immunology, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/b6c8da625a5ddb2180537d9e8c970042c34f663e

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Citations in the corpus

Apoptosis: A Review of Programmed Cell Death (2007, background): “The appearance of phosphotidylserine on the outer leaflet of apoptotic cells then facilitates noninflammatory phagocytic recognition, allowing for their early uptake and disposal (Fadok et al., 2001).”
Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. (2005, positive): “Uptake of undifferentiated apoptotic PLB- 985 cells is decreased compared to differentiated, PSexposing cells, supporting the role of PS in engulfment ( Fadok et al., 2001b ).”
Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-beta1 secretion and the resolution of inflammation. (2002, methodology): “To examine this requirement in vivo, the human monomyelocyte cell line PLB-985 was employed since it has been shown to not express PS on the surface during ultravioletinduced apoptosis (31).”
Identification of a factor that links apoptotic cells to phagocytes (2002, background): “Cells repleted with PS can be recognized by phagocytes as target”